Lee, Sven J. van der

ABSTRACT Genetic variation at the TMEM106B locus has been associated with Alzheimer’s disease (AD) and related neurodegenerative phenotypes, yet its haplotypic architecture remains incompletely resolved. We refined the genetic landscape of TMEM106B by integrating AD-GWAS summary statistics (∼978K individuals) with haplotype analyses in 5,873 Dutch genomes including AD-cases, age-matched controls, and cognitively healthy centenarians. In addition to the known linkage disequilibrium (LD) block defining risk and protective haplotypes characterized by the amino acid substitution at residue 185 (Threonine/Serine), we identify a second conditionally independent LD block. Together these form four haplotypes (T1-T4), with T3 strongly enriched in centenarians. Long-read whole-genome sequencing in 493 individuals reveals haplotype-linked structural variation and methylation patterns, including a ∼19 Kbp genomic rearrangement carried by T3. These findings indicate that the TMEM106B locus comprises multiple haplotypes defined by methylation patterns and structural variants, offering insights into GWAS associations with AD risk and preserved cognition at extreme age.

AbstractBackgroundThe TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome‐wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD‐TDP). However, the causal variant that drives the association has thus far remained elusive.MethodsWe generated long‐read whole‐genome sequencing data of 256 individuals, primarily from Dutch descent. We characterized SNPs and larger structural variants in the TMEM106B locus using de novo genome assembly.ResultsWe identified an insertion of an AluYb8 retrotransposon in the 3’ UTR of TMEM106B gene, that was in complete linkage with the TMEM106B risk‐SNP. AluYb8 retrotransposons have the propensity to propagate through our genomes by utilising a ‘copy‐paste’ mechanism, and once integrated can disrupt transcription and translation of nearby genes. However, propagation of retrotransposons can be suppressed by methylation of the insert and its surrounding regions. Indeed, we observed that the risk haplotype with the AluYb8 insertion, but not the protective haplotype, accumulated CpG islands over evolutionary time. Notably, we observed similar retrotransposon insertions in the 3’ UTR of TMEM106B orthologs in non‐primate species. This suggests a survival advantage, which may be explained by recent findings that TMEM106B is an entry‐receptor for specific viruses in lung‐tissue, such that SINE‐mediated downregulation of TMEM106B may limit viral infection‐load across species.ConclusionsWe speculate that AluYb8‐mediated downregulation of TMEM106B may be protective at younger ages in lung tissues, but that at advanced ages its downregulation in the brain may contribute to increased risk of neurodegenerative diseases. Furthermore, next to the supression of AluYb8 activation by DNA methylation, it may also be suppressed by TDP‐43, in its role in post‐translational RNA‐processing. This leads us to further speculate that age‐related demethylation and age‐related dysregulation of TDP‐43 may result in a negative feedback loop that ultimately reduces the endolysosomal activity in cells. We argue that such a mechanism would explain why increased age is among the strongest risk factors of neurodegenerative diseases.

Abstract Aims Although the neuroanatomical distribution of tau and amyloid‐β is well studied in Alzheimer's disease (AD) (non)‐amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid‐β and phosphorylated tau in a clinically well‐defined prospectively collected AD cohort. Methods Clinical variants were diagnosed antemortem, and brain tissue was collected post‐mortem. Typical AD ( n = 10), behavioural/dysexecutive AD ( n = 6), posterior cortical atrophy (PCA) AD ( n = 3), and controls ( n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid‐β, CD68, MHC‐II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology. Results Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid‐β was neocortical‐dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE‐NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC‐II were hippocampal‐dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC‐II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants. Conclusions Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation‐based biomarkers and future therapeutics.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Abstract Introduction There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results Single‐variant analysis identified associations with apolipoprotein E ( APOE ) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP , PSEN2 , CCK , and ZNF397 . There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD.